1. Field
Provided is an anti-Ang2 antibody or an antigen-binding fragment thereof that specifically binds to an angiogenesis-inducing factor Angiopoietin-2 (Ang2) and complexes with a Tie2 receptor when bound to Ang2, and a use for prevention and/or treatment of a disease accompanied by vascular leakage and/or vascular inflammation.
2. Description of the Related Art
Angiopoietin-2 (Ang2) is an antagonistic ligand of a receptor Tie2 present at vascular endothelial cells. It is believed to suppress signaling by Tie2 by competing with Angiopoietin-1 (Ang1), which is an agonist of Tie2, to bind to Tie2. Ang1, which is a ligand activating the Tie2 receptor, functions as a key regulator of maintaining the stabilization of blood vessels by maintaining the barrier function of vascular endothelial cells. The vascular endothelial cells are activated, demonstrated by the overexpression of VEGF or inflammation, and vascular permeability is increased. It is thought that Ang1 induces the stabilization of vascular endothelial cells and reduces vascular permeability by accelerating the junctional integrity of the vascular endothelial cells whereas Ang2 which is increased in the activated vascular endothelial cells serves to suppress the stabilization of the vascular endothelial cells by Ang1 by competing with Ang1. Therefore, Ang2 inhibits Ang1-Tie2 binding which maintains the stability of the vascular endothelial cells and signaling thereby, thus ultimately accelerating angiogenesis via the dynamic rearrangement of blood vessels.
As angiogenesis is an important element for the growth of cancer, preventing the additional growth of cancer by inhibiting the function of Tie2-dependent Ang2 to suppress angiogenesis has been known by the research of several preclinical models and in fact, various attempts to prevent the progress of cancer using anti-Ang2 antibodies are ongoing.
The overexpression of Ang2 in a variety of solid cancers and blood cancers has been reported, and Ang2 expression in a serum often serves as a biomarker of poor prognosis. The overexpression of Ang2 has been reported not only in the cancers but also in various diseases including sepsis, bacterial infection, lung injury and kidney injury, and of them, its correlation with vascular leakage has been vigorously studied. Due to the correlation with such pathological conditions, Ang2 has been considered to be an important target in therapeutic intervention. Currently, a variety of drugs being developed are in their clinical or preclinical stages, and they have a variety of forms including a peptibody, bispecific antibody, monoclonal antibody, etc.
However, most of the Ang2-target drugs have mechanisms of suppressing the activation of a Tie2 receptor and its downstream signaling by inhibiting Ang2 from binding to the Tie2 receptor. Therefore, the pre-existing Ang2-target drugs cannot be expected to perform vascular normalization by Tie2 receptor and its downstream signaling.